Project Summary Alzheimer?s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. It afflicts an evergrowing number of individuals with devastating consequences. Key features of AD pathology are amyloid plaques holding pathological forms of Ab and neurofibrillary tangles containing hyperphosphorylated Tau. Human association and animal studies suggest that obesity and the accompanying metabolic syndrome are risk factors for AD. The mechanisms underlying these putative effects of metabolic dysfunction remain poorly understood and warrant examination considering that obesity is a global health problem. Our previous studies identified a critical role for brain-derived neurotrophic factor (BDNF) in central neural circuits controlling energy and glucose balance. The parent grant for this administrative supplement application investigates whether BDNF signaling through the truncated form of the TrkB receptor (TrkB.T1) in astrocytes in the ventromedial hypothalamus (VMH) is one mechanism mediating energy balance and body weight control. The data so far indicate that TrkB.T1 in VMH astrocytes inhibits expression of the astrocytic glutamate transporter GLT-1 and synaptic glutamate clearance. This effect elevates the excitatory tone onto anorexigenic VMH neurons and suppresses appetite. Moreover, we found that chronic intake of a high fat diet in normal mice elevates expression of TrkB.T1 in hippocampus and prefrontal cortex (PFC), two brain regions involved in cognitive function and affected in AD. These findings are relevant to AD because elevated and reduced levels of TrkB.T1 and GLT-1, respectively, have been reported in AD brain. We hypothesize that HFD-induced obesity and Ab accumulation cooperate to increase levels of TrkB.T1 in cortical and hippocampal astrocytes. TrkB.T1, for its part, impedes synaptic glutamate clearance and the consequent accumulation of extracellular glutamate elicits synaptic dysfunction, exitotoxicity, neurodegeneration and ultimately, cognitive decline. To test this idea, we propose a series of studies examining the effects of HFD consumption on TrkB.T1 in astrocytes and on glutamate uptake kinetics in hippocampus and PFC of a mouse model of AD. Findings from these investigations will serve as a foundation for future studies informing the relationship between obesity and the onset of AD.